PROJECT SUMMARY PROJECT 4 ? COCAINE IVSA Evidence from both human and animal studies indicates that a multitude of traits, including novelty seeking, novelty preference, disruptions in circadian rhythms, prior drug exposure, and impulsivity are strongly correlated with the propensity to develop a substance use disorder, suggesting that in many cases, a common biological mechanism for these predictive phenomena and drug self-administration. We propose to identify biological mechanisms of addiction and predisposing behavior by harnessing recent advances in mouse genetic resources including the genetically diverse Collaborative Cross (CC) reference panel, the high- precision Diversity Outbred (DO) mouse population, and the computational and statistical methods in systems genetics developed to analyze these populations. Project 4 provides critical data for the correlation of multiple risk factors for vulnerability to cocaine self-administration. We will utilize male and female mice from the inbred CC and founder strains to quantify heritability and genetic correlations among predisposing novelty-related behaviors and intravenous cocaine self-administration, as well as their relationship with other heritable addiction-related behaviors assessed in the Center for Systems Neurogenetics of Addiction (CSNA), which include impulsivity, nicotine conditioned place preference (CPP), circadian rhythms, and cocaine sensitization. Intravenous drug-self administration (IVSA), considered the gold standard for the assessment of addiction in preclinical research, will enable quantification of the core features of addiction including compulsive drug use, difficulty limiting drug intake and an extremely high motivation to take the drug. We will evaluate genetic correlations among behavioral phenotypes (novelty-related traits, cocaine IVSA) and the expression of genes and gene networks in CC mice. Gene co-expression networks, QTL positional candidates and behavioral correlates of gene expression will be compared with other functional genomics data to refine and characterize candidate genes and biological mechanisms. Behaviorally relevant expression mechanisms will be genetically mapped in DO mice to independently identify putative candidate genes for novelty-related traits and cocaine IVSA that act through transcriptional regulation of other relevant genes. We will use a large population of DO mice to map behavioral QTLs?and identify candidate genes?that influence cocaine IVSA and predisposing novelty-related behaviors. The most compelling and tractable of these candidate genes and mechanisms will be validated in mutant mice.